Chronically elevated sympathetic neural activity is a characteristic of many disease states. Tonic chemoreflex activation has been implicated in the development of sympathetic overactivity; however, other reflexes may also contribute. For example, in an animal model, stimulation of pulmonary baroreceptors induces a reflex increase in sympathetic neural activity. In humans, pulmonary pressure has been shown to be related to basal sympathetic activity in pulmonary hypertension; however a critical step in determining a causal link is to establish whether changing pulmonary pressure alters sympathetic outflow. In this pilot study, we exposed thirteen healthy humans (5 females, 28 [ ± 7] years) to high altitude hypoxia (HA; 4383m), a setting known to increase both pulmonary pressure and sympathetic activation, before selectively lowering pulmonary pressure via inhalation of the pulmonary vasodilator nitric oxide. Muscle sympathetic nerve activity (MSNA; Microneurography), blood pressure (BP; Photoplethysmography), heart rate (HR; Electrocardiogram), and peripheral oxygen saturation (SPO2; Pulse oximetry) were continually measured during ambient air breathing (Amb) and during a 6-minute inhalation of nitric oxide (iNO; 40ppm in 21% O2). Pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR) and stroke volume (SV) were determined via cardiac ultrasound. iNO reduced PASP (−23 ± 12%) and PVR (−21 ± 16%) compared to Amb (Table 1). iNO also reduced MSNA burst frequency (−18 ± 18%), burst incidence (−16 ± 17%) and total activity (−21 ± 20%) compared to Amb. MSNA changes during iNO were not related to changes in SPO2 (r = −0.16, P = 0.61) or MAP (r = −0.28, P = 0.35). Our data demonstrate that selectively reducing pulmonary pressure reduces sympathetic nerve activity in healthy humans; therefore, this provides evidence for a causal link in the relationship between pulmonary pressure and basal sympathetic activity. Further investigation is warranted to establish whether elevated pulmonary pressure is a mechanism contributing to chronically elevated sympathetic outflow in disease.